Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins

Context. Increased levels of homocysteine are associated with risk of cardi ovascular disease. Homocysteine may cause this risk by impairing endothelia l cell function. Objective. To evaluate the effect of acute hyperhomocysteinemia with and wi thout antioxidant vitamin pretreatment on cardiovascular risk factors and e ndothelial functions. Design and Setting. Observer-blinded, randomized crossover study conducted at a university hospital in Italy. Subjects. Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years. Interventions. Subjects were given each of 3 loads in random order at 1-wee k intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins. Main Outcome Measures. Lipid, coagulation, glucose, and circulating adhesio n molecule parameters, blood pressure, and endothelial functions as assesse d by hemodynamic and theologic responses to L-arginine, evaluated at baseli ne and 4 hours following ingestion of the loads. Results. The oral methionine load increased mean (SD) plasma homocysteine l evel from 10.5 (3.8) mu mol/L at baseline to 27.1 (6.7) mu mol/L at 4 hours (P < .001). A similar increase was observed with the same load plus vitami ns (10.0 [4.0] to 22.7 [7.8] mu mol/L; P < .001) but no significant increas e was observed with placebo (10.1 [3.7] to 10.4 [3.2] mu mol/L; P = .75). C oagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone (P < .05) but not after placebo or methio nine ingestion with vitamins. While the mean (SD) blood pressure (-7.0% [2. 7%]; P < .001), platelet aggregation response to adenosine diphosphate (-11 .4% [4.5%]; P = .009) and blood viscosity (-3.0% [1.2%]; P = .04) declined in these parameters 10 minutes after an L-arginine load (3 g) following pla cebo, the increase after methionine alone (-2.3% [1.5%], 4.0% [3.0%], and 1 .5% [1.0%], respectively; P < .05), did not occur following methionine load with vitamin pretreatment (-6.3% [2.5%], -7.9% [3.5%], and -1.5% [1.0%], r espectively; P = .24). Conclusion. Our data suggest that mild to moderate elevations of plasma hom ocysteine levels in healthy subjects activate coagulation, modify the adhes ive proper ties of endothelium, and impair the vascular responses to L-argi nine. Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism.